HER2 protein expression patterns in gallbladder adenocarcinoma and extrahepatic cholangiocarcinoma

Gallbladder adenocarcinoma (GBCa) and extrahepatic bile duct cholangiocarcinoma (ECCa) are aggressive malignancies. For unresectable, locally advanced, or metastatic disease, systemic therapy is the only treatment option. Survival rates remain dismal, thus a better understanding of their molecular biology and study of potential targeted therapies are important unmet needs. The tissue agnostic approval of HER2-targeted therapy for medications such as trastuzumab-deruxtecan (T-DXd) for tumors with strong (3+) HER2 expression by immunohistochemistry has motivated interest in HER2 expression among these tumor types. We sought to study the frequency and clinicopathologic features of HER2 expression in GBCa and ECCa. A 14-year retrospective analysis was performed on GBCa and ECCa, including metastatic cases. HER2 immunohistochemistry (Ventana, clone 4B5) was performed on eligible cases and interpreted using the CAP/ASCO gastroesophageal adenocarcinoma scoring guidelines. Clinicopathologic features were assessed with respect to HER2 immunoreactivity, and HER2 scoring agreement was calculated using weighted kappa statistics. There were 59 total cases (GBCa n = 43, ECCa n = 16), with five cases demonstrating strong (3+) HER2 reactivity (8.5%), 22 cases showing 1 + or 2 + immunoreactivity (37.3%), and 32 with a score of 0 (54.2%). HER2 score was higher in metastases compared to corresponding primaries in 7/18 events (38.9%). Among factors considered, histologic grade differed most significantly by HER2 score, with negative cases more likely to be poorly differentiated (p = 0.006). HER2 status was not significantly associated with clinical outcomes (3-year PFS, all-cause mortality). The study describes the frequency and clinicopathologic correlates of HER2 expression in gallbladder adenocarcinoma and extrahepatic cholangiocarcinoma.